X-Linked Adrenoleukodystrophy - Type, Symptoms, and Treatment

Introduction:

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder affecting the nervous system, adrenal glands, and consequently the brain and the spine. It is caused by a gene mutation in the ABCD1 on the X-chromosome. X-ALD can affect males and females, though the symptoms tend to be more severe in males. This article covers the various X-ALD types, associated symptoms, and possible causes.

What Is X-Linked Adrenoleukodystrophy?

X-linked adrenoleukodystrophy (X-ALD) is a very uncommon genetic disorder that affects the brain, nervous system, and adrenal glands, which are located on the top of each kidney. A gene mutation causes it in the ABCD1 on the X chromosome. X-ALD is an inherited condition that can affect both males and females, but it tends to be more severe in males due to its genetic link to the X chromosome.

In X-ALD-affected individuals, the protective myelin sheath (fatty covering) surrounding nerve cells in the brain and spinal cord starts to deteriorate (demyelination), leading to progressive neurological impairment and damage. Myelin loss reduces the nerve's ability to transmit information to the brain. Furthermore, damage to the outer layer of the adrenal glands (adrenal cortex) results in a lack of certain hormones (adrenocortical insufficiency). They can lead to various symptoms, including weakness, weight loss, skin changes, vomiting, and coma.

What Are the Types of X-Linked Adrenoleukodystrophy?

There are four main types of X-linked adrenoleukodystrophy:

• Adrenomyeloneuropathy (AMN).

• Adult cerebral ALD.

• Childhood cerebral ALD.

• Addison’s-only ALD.

• Adrenomyeloneuropathy (AMN): This X-linked adrenoleukodystrophy (ALD) is the most common, less severe, and slowly progressive type and affects adult males. The primary symptoms are progressive spinal cord and peripheral nervous system degeneration, resulting in difficulty walking (stiff gate), bladder problems, and impaired sensory function. In some cases, cognitive impairment and hearing loss can also be present. Females who are carriers of adrenoleukodystrophy may develop a mild form of AMN.

• Adult Cerebral ALD: This type of ALD is characterized by white matter degeneration in the brain, which can cause various neurological symptoms, including seizures, dementia, personality changes, motor weakness, gait disturbance, and hearing loss.

• Childhood Cerebral ALD: Also known as childhood cerebral X-linked adrenoleukodystrophy (CCALD), this ALD usually occurs in boys between four and ten. Symptoms can include intellectual disability, seizures, learning difficulties, visual impairment, hearing loss, difficulty speaking, and behavioral changes. Progressive harm is being done to the brain's white matter. If it is not treated early, it may lead to death within five to ten years.

• Addison’s-Only ALD: This rare form of ALD is characterized by a deficiency of the adrenal glands, which results in an inability to produce cortisol and aldosterone hormones. Common symptoms include fatigue, dizziness, weight loss, skin changes, and low blood pressure.

What Are the Causes of Adrenoleukodystrophy?

The inherited disorder, X-linked adrenoleukodystrophy (X-ALD), is caused by a mutation in the ABCD1 gene on the X chromosome. The ABCD1 gene provides instructions for making an enzyme called ALDP (adrenoleukodystrophy protein). This enzyme helps break down very long chain fatty acids (VLCFAs), which are fatty acids that contain more than 20 carbon atoms, into peroxisomes. Peroxisomes are tiny sacs within the cells that produce many molecules, including VLCFs. When the ABCD1 gene is mutated, it does not produce enough of the ALDP enzyme, resulting in an accumulation of VLCFAs. This accumulation can cause progressive damage to the myelin sheath that protects nerve cells in the brain and other organs in the body. This damage leads to symptoms of X-ALD.

What Are the Symptoms Of X-Linked Adrenoleukodystrophy?

X-linked adrenoleukodystrophy (X-ALD) is an uncommon genetic disorder that affects males but can also sometimes occur in females. Symptoms vary depending on the type of X-ALD present. Still, some of the most common signs and symptoms include the following:

Adrenomyeloneuropathy (AMN) is a specific X-ALD form and usually appears from early adulthood to middle age. Common signs and symptoms of AMN include:

• Weakness and stiffness in the legs (spastic paraparesis).

• Urinary incontinence- Problems with bowel and bladder control because of sphincter dysfunction.

• Decreased sex drive (erectile dysfunction).

• Painful muscle spasms.

• Weight gain.

• Fatigue.

• Abnormal gait (unusual walk-in manner).

Childhood cerebral adrenoleukodystrophy (CALD) is the second most common type of X-ALD and typically occurs in boys and affects children between the ages of 4 and 10. Common symptoms of CALD include:

• Difficulty in reading and writing.

• Behavioral changes.

• Seizures.

• Cognitive deficits.

• Loss of vision.

• Deafness.

• The trouble with speaking.

Adrenoleukodystrophy (ALD): ALD is another type of X-ALD and usually affects older males. Symptoms of ALD can include:

• Decreased coordination and balance.

• Difficulty walking.

• Impaired speech.

• Confusion and personality changes.

Addison’s Disease: Addison’s Disease is the fourth most common type of X-ALD and typically affects older males. Symptoms of Addison’s disease can include:

• Loss of intellectual function (dementia).

• Psychiatric disorder.

• Fatigue.

• Muscle weakness.

• Nausea.

• Decreased appetite.

• Weight loss.

• Skin darkening.

In adults, cerebral ALD of X-ALD can affect both men and women. Common symptoms of ACALD can include vision impairment, seizures, impaired hearing and speech, difficulty walking, difficulty coordinating movements, and problems with memory and learning. Women with ALD may also experience fertility issues and menstrual abnormalities.

How to Diagnose Adrenoleukodystrophy?

X-linked adrenoleukodystrophy is typically diagnosed through genetic testing, imaging, and other specialized tests.

• Blood Testing - A blood test is typically used to measure a high level of very long-chain fatty acids, which are the key indicator and can be elevated in individuals with X-linked adrenoleukodystrophy. Doctors also use a blood sample to identify the genetic mutations that can lead to ALD. They also evaluate the adrenal gland's functioning through blood testing.

• MRI (Magnetic Resonance Imaging): Strong magnets and radio waves create detailed images of the brain as they can help detect abnormal changes, including damage to the white matter of the nerve tissue in the brain.

• Vision Screening: Other specialized tests, such as vision screening measuring visual responses in men with no other symptoms, can help track disease progression.

• The Skin Biopsy and Fibroblast Cell Culture Test: involves extracting a small skin sample from the patient and then culturing the cells in the laboratory to measure the level of very long-chain fatty acids. This test is particularly useful for individuals suspected to have mild forms of the disorder, as their blood tests may not reveal high levels of fatty acids.

• Genetic Testing: It can help to confirm a diagnosis of X-linked adrenoleukodystrophy. Genetic testing looks for specific mutations in the ABCD1 gene, which is known to be associated with this condition. Once a mutation is identified, the diagnosis is considered confirmed.

How to Treat the X-Linked Adrenoleukodystrophy?

There is no cure for adrenoleukodystrophy. However, stem cell transplantation may be able to halt the progression of ALD if done when neurological symptoms appear first.

• Stem Cell Transplant (SCT): A stem cell transplant is a primary treatment for X-linked adrenoleukodystrophy (X-ALD). This procedure involves removing some of the patient's blood stem cells from their bone marrow and injecting them into their bloodstream after being treated with chemotherapy to destroy the diseased cells. The goal of this transplant is to replace the defective X-ALD gene with a healthy gene from a donor, allowing the patient's body to produce the enzyme needed for proper fatty acid metabolism.

• Adrenal Insufficiency Treatment: People with ALD develop adrenal insufficiency and need to regulate adrenal gland testing, which can be managed with steroids and lifestyle changes. Corticosteroids can treat inflammation, while fludrocortisone can help regulate the body's electrolyte levels.

• Medication: The doctor may prescribe the medication to manage symptoms, including seizures and stiffness.

• Physical Therapy: Physical therapy is also recommended to maintain muscle strength and improve range of motion. Additionally, occupational therapy can help the patient adapt to any physical limitations caused by the disorder.

Low-fat diets and supplementation with omega-3 fatty acids may be suggested. In some cases, dietary changes are also recommended to manage X-ALD symptoms. However, it is important to consult a physician before making any drastic dietary changes.

Conclusion

X-linked adrenoleukodystrophy is a genetic condition that affects the nervous system, adrenal glands, and immune system. It is caused by mutations in the ABCD1 gene located on the X chromosome, which is why it affects males primarily. Symptoms of X-ALD can include fatigue, neurologic problems, muscle weakness, and vision impairment. Diagnosis is based on medical history, physical examination, genetic testing, and imaging studies. Treatment for X-ALD may include medication, dietary modifications, physical therapy, and stem cell transplantation. Although there is no cure for X-ALD, early diagnosis and treatment can help improve the prognosis and quality of life for individuals affected by this condition.